Can the NK Family of Osteoblast Homeodomain Transcription Factors Signaling Be a Magic Bullet to Reverse Calcification-Induced Vasculopathy in Diabetes?

Human vascular calcification burden has existed for at least 5 millennia and has long been a major area of interest in the cardiovascular physiopathology research. Abnormal calcium deposition occurs in almost all arterial beds in both the media and intima in metabolic and diabetic diseases. Calcification of arteries reduces arterial elastance and compromises cardiovascular hemodynamics, which are high risk factors for cardiovascular diseases such stroke and ischemic heart disease (1). Despite the wealth of information regarding the effects of vascular calcification in atherosclerosis, metabolic syndrome, hypertension, and diabetes, the molecular mechanism of arteriosclerosis remains poorly understood. Therefore, understanding the mechanism by which diabetes and metabolic disease induce vascular calcification is crucial to identify effective new therapeutic strategies to intervene with the disease. Interestingly in this issue, Cheng et al. (2) determined the in vivo contribution of members of the highly conserved NK family of osteoblast homeodomain transcription factors 1 (Msx1) and 2 (Msx2) signaling in arteriosclerosis and vascular stiffness in diabetic mice. The study by Cheng et al. provides new insight into the molecular mechanism that drives arteriosclerosis in diabetes and suggests a potential target for future therapy. Thus, targeting Msx1 and Msx2 would substantially help the development of a new therapeutic strategy to overcome calcification-induced vasculopathy.

In diabetic patients, vascular calcification occurs mainly in coronary and vascular arteries of lower limbs (3,4). This calcification is associated with an increased prevalence of arteriosclerosis vascular disease and cardiovascular morbidity and mortality. Arteriosclerosis is the thickening, hardening, and loss of elasticity of arterial walls in diabetes, dyslipidemia, and uremia (5). The calcification of arterial media, called Mönckeberg sclerosis or arteriosclerosis, is a characteristic feature of diabetes. Arterial media calcification is a concentric and dynamic process of the tunica media, which compromises vascular homeostasis and represents a high risk factor for cardiovascular diseases (6).

Recent evidence indicates that medial calcification in diabetes is an active, cell-mediated process in which vascular smooth muscle cells (VSMCs) express a number of bone matrix proteins involved in the calcification events. Cheng et al. (2) reported that Msx1 and Msx2 play an in vivo important role in vascular calcification. Thus, the inhibition of Msx1 and Msx2, specifically in smooth muscle cells and vascular myofibroblast, using a Cre-Lox knockout mice system substantially reduced aortic calcium deposition and improved pulse wave velocity (an index of stiffness). These events are associated with a reduction in transcription factors essential for osteogenic alleviation of mineralization, osterix, and Sonic hedgehog (Shh) (a marker of the vascular multipotent mesenchymal progenitors). Importantly, the study reported that mice deficient for Msx1 and Msx2 in VSMCs exhibit a significant reduction in aortic calcium accumulation after 2 months of high-fat diabetogenic diet treatment compared with control mice fed with high-fat diet. The same group previously demonstrated in the same model of murine diabetic arteriosclerosis that Msx1 and Msx2 expressions are upregulated in the aorta in LDL receptor^−/− mice fed with high-fat diet (7), indicating that Msx1 and Msx2 are linked to the calcification events that occur in diabetes. Most important, Cheng et al. showed that reducing arterial Msx1 and Msx2 expression attenuates vascular stiffness in a murine model of high-fat diet−induced diabetic arteriosclerosis. Moreover, the authors elucidated that Msx1- and Msx2-deficient mice exhibit deficiencies in transcription markers of early osteogenic and adipogenic differentiation in aortic adventitial myofibroblasts, indicating that Msx are important regulators for vascular calcification. Surprisingly, the conditional deletion of Msx2 alone was not sufficient to lower aortic calcium deposition in response to a high-fat−diet challenge, which may indicate the necessity of interaction between Msx1 and Msx2 and/or the downstream signaling in the calcium deposition. In term of the mechanistic, the Msx1 and Msx2 more likely dictate aortic adventitial osteoprogenitors through Wnt signaling and Shh gene–dependent mechanisms.

Cheng et al. (2) reported that inhibition of vascular Msx reduces aortic calcium accumulation and vascular stiffness, while aortic collagen accumulation and vascular wall thickness were unchanged. These results may suggest a new pathway independent of collagen accumulation and vascular wall thickness. This is the first study showing the in vivo contribution and importance of Msx as crucial factors in vascular calcium deposition and osteoprogenitor homeostasis. Cheng et al. presented clear evidence of the importance of Msx genes linked to Wnt gene expression in diabetic arteriosclerosis (Fig. 1). Thus, it would be very interesting to determine what regulates Msx expression in diabetes and the cause-effect between Msx and Wnt isoforms in the osteogenic differentiation.

In summary, the study by Cheng et al. (2) delineates a new paradigm, indicating that reduction in vascular calcification with concomitant reduction in arterial stiffness can be successfully achieved via the in vivo inhibition of arterial Msx1 and Msx2 signaling. These results indicate that Msx1 and Msx2 could be potential targets to rescue vascular function and structure and reduce morbidity and mortality in diabetes related to vascular calcification. Further studies are needed to determine the mechanisms that enhance Msx1 and Msx2 expression in diabetes and to elucidate specific partners targeted by Msx1 and Msx2 that dictate vascular calcification in diabetes and metabolic disease. It would be interesting to determine the potential contribution of hyperglycemia, insulin resistance, and dyslipidemia in Msx1 and Msx2 expression regulation in diabetes and metabolic diseases. Currently, no therapeutic strategy is available to reverse vascular calcification in diabetes. Available therapy can only lower or slow the progression of vascular calcification. Thus, the novelty that targeting Msx signaling (regulation of osteogenesis) reduces vascular calcification might provide new avenues for new therapeutic approaches to reverse calcification-induced vasculopathy.